Effervescent compositions comprising bisphosphonates and methods related thereto

ABSTRACT

The invention provides effervescent composition comprising a bisphosphonate, an acidic compound, an alkaline effervescing component, and optionally an anti-ulcer agent and methods of treating osteoporosis in a mammal using the effervescent compositions.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

[0001] This patent application is a continuation-in-part of copendingU.S. patent application No. 10/092,083, filed Mar. 6, 2002.

TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates generally to effervescentcompositions. More particularly, the invention pertains to effervescentcompositions comprising a bisphosphonate, and is particularly useful inthe treatment of osteoporosis.

BACKGROUND OF THE INVENTION

[0003] Osteoporosis is a disease that leads to defective skeletalfunction caused by low bone mass and deterioration of bone quality. Inthis respect, bone characterized by weakened mechanical strength is muchmore susceptible to fracture, even under stresses that would otherwisebe tolerated by normal bone. In the United States alone, some 8 millionwomen and 2 million men suffer from osteoporosis. Many more are atincreased risk for osteoporosis because they have low bone mass. Therisk of suffering from osteoporosis increases with age, particularly inthose over the age of 50.

[0004] Osteoporosis results from a disorder in bone remodeling, which isthe process by which bone tissue is continually renewed and repaired. Inbone remodeling, osteoclasts resorb old or damaged bone, whileosteoblasts synthesize a new bone matrix. In patients who suffer fromosteoporosis, the rate of bone resorption undesirably exceeds the rateof bone formation, either because too much bone is resorbed or toolittle bone is formed.

[0005] Drugs used in the treatment of osteoporosis act by inhibitingbone resorption. Among such anti-resorptive agents are bisphosphonatecompounds. Bisphosphonates are synthetic analogues of pyrophosphates,which are naturally occurring regulators of bone turnover.

[0006] Bisphosphonates, like pyrophosphates, can bind to the surface ofthe hydroxyapatite bone matrix. It will be appreciated by the ordinarilyskilled artisan that the pharmacologic properties of bisphosphonates canbe varied through side chain substitutions (R¹, R²) on their generalchemical structure. For example, alendronate has an amino side chain(R²═CH₂CH₂CH₂NH₂) while risedronate has a cyclic nitrogen-containingside chain. The R¹ and R² side chains for a variety of bisphosphonatecompounds are given in Table 1. TABLE 1 Bisphosphonate R¹ side chain R²side chain Etidronate OH CH₃ Clodronate Cl CI Pamidronate OH CH₂CH₂NH₂Alendronate OH (CH₂)₃NH₂ Risedronate OH CH₂-3-pyridyl Tiludronate HCH₂-S-phenyl-Cl Ibandronate OH CH₂CH₂N(CH₃)(pentyl) Zoledronate OHCH₂-imidazole YH529 OH CH₂-2-imidazopyridinyl Incadronate HN-(cycloheptyl) Olpadronate OH CH₂CH₂N(CH₃)₂ Neridronate OH (CH₂)₅NH₂EB-1053 OH CH₂-1-pyrrolidinyl

[0007] The oral administration of bisphosphonate compounds for thetreatment of osteoporosis suffers from several major drawbacks. First,bisphosphonate compounds are very poorly absorbed from thegastrointestinal tract into the blood of a patient (e.g., have lowbioavailability). In fact, typically only about 0.5% to about 5% of thetotal bisphosphonate active ingredient is absorbed from an oral dosageformulation (e.g., a solid tablet). Once in the blood stream, typicallyonly about 20% to about 50% of the bisphosphonate becomes bound to thebone surface. The bioavailability of bisphosphonate is further reducedunder highly acidic gastric conditions, which occur when the patient haseaten food or consumed an acidic beverage (e.g., coffee, tea, or orangejuice).

[0008] The bioavailability of the bisphosphonate is further affected bythe delivery system. Solid delivery systems such as capsules and tabletsmust be ingested with sufficient liquid to disintegrate the dosage form.Once the dosage form is inside the stomach or small intestine of apatient, it has to disintegrate into small particles, and the activeingredient has to be solubilized such that it can be absorbed into theplasma of the patient. The disintegration and solubilization processesfor solid dosage forms delay the bioavailability of the activeingredient.

[0009] Effervescent drug formulations can offer enhanced dissolution andabsorption of active ingredients resulting in increased bioavailability.Frequently, active ingredients are absorbed better from effervescentformulations as compared to dry, solid tablet formulations. Effervescenttablets also can be larger in size allowing for higher drug loading aswell as combination drug loading. Because the tablets are dissolved inwater, they are easier to swallow than dry solid tablet formulations.Furthermore, effervescent compositions can be formulated withoutpolyvalent metal ions (e.g., Ca²⁺ and Mg²⁺), which can bind tobisphosphonate compounds rendering them insoluble and unabsorbable. Aneffervescent bisphosphonate composition is disclosed in U.S. Pat. No.5,853,759 which describes an effervescent tablet comprising abisphosphonate, in particular alendronate, an acid component, and analkaline effervescing component.

[0010] A second drawback, even with effervescent formulation, oftenencountered by patients taking regular dosages of bisphosphonates is thecommon occurrence of upper gastrointestinal disturbances. Suchdisturbances include heartburn, esophageal irritation, and even, in somecases, esophageal ulcers. The local tissue irritation and ulcerationassociated with the administration of bisphosphonates may be mitigatedby the administration of drugs that suppress gastric acid production.Anti-ulcer agents such as H₂-antagonists (i.e., histamine H₂-receptorantagonists) and proton pump inhibitors are known to be effective incombating acid-peptic diseases. Proton pump inhibitors (e.g., H⁺,K⁺-ATPase inhibitors) are α-pyridylmethylsulfinyl benzimidazolecompounds having different pyridine or benzimidazole substituents. Theproton pump inhibitors react with acid (are activated) to formthiophilic sulfenamide or sulfenic acid components. Once activated, thecompounds irreversibly bind to the sulfhydryl group of cysteine residuesthus halting acid production. Commercially available H₂-antagonistsinclude cimetidine (Tagamet®), ranitidine (Zantac®), famotidine(Pepcid®), and nizatidine (Axid®). The H₂-antagonists inhibit acidproduction by competing with histamine in binding to H₂-receptors.

[0011] The combination of these problems has led to a complicatedregimen that attempts to optimize bioavailability of the bisphosphonatewhile minimizing the gastrointestinal problems. Thus, current regimensrequire the patient to (a) remain strictly upright for at least 30minutes after taking the bisphosphonate composition so as to minimizeesophageal irritation, and (b) wait as much as 2 hours before eating.

[0012] U.S. Pat. Nos. 5,994,329, 6,015,801, 6,225,294, and 6,333,316 aswell as EP 1 127 573 A1 disclose methods for inhibiting bone resorptioncomprising sequential administration of histamine H₂ receptor blockersand/or proton pump inhibitors about 30 minutes to about 24 hours priorto administration of bisphosphonates. Administration of such histamineH₂ receptor blockers and/or proton pump inhibitors in this mannerexacerbates the already complicated and inconvenient regimen because thepatient would have to take the histamine H₂ receptor blockers and/orproton pump inhibitors (e.g., upon waking), then wait 30 minutes orlonger to take the bisphosphonate and then wait up to 2 more hours toeat.

[0013] Despite the availability of the foregoing approaches, it will beappreciated that there remains a need in the art for compositions anddrug administration regimens for osteoporosis, or other bone resorptiondisorders, which are less complicated and more convenient than thosecommonly known in the art. Moreover, there remains a need for acomposition that can deliver a bisphosphonate drug for treatingosteoporosis (or other bone resorption disorders) while reducingassociated ulceration. The invention seeks to provide such compositionsto satisfy at least one of these needs. These and other advantages ofthe invention will be apparent from the description of the inventionprovided herein.

BRIEF SUMMARY OF THE INVENTION

[0014] The invention provides an effervescent composition comprising abisphosphonate, which upon dissolution in water has a buffered pH. Inaccordance with the present invention, it has been found that includinga bisphosphonate in such an effervescent composition imparts improvedbioavailablity of the bisphosphonate to the body of a mammal. Desirably,the effervescent composition of the invention, when orally administeredto a mammal, preferably raises the pH of the gastric juices of thestomach of the mammal to a pH of about 3 or more.

[0015] Thus, in one aspect, the present invention provides aneffervescent composition comprising a bisphosphonate, an acid component,and an alkaline effervescing component such that the composition, whendissolved in water, produces a solution having a buffered pH of about 3to about 6.5.

[0016] In another aspect, the present invention provides an effervescentcomposition that comprises a bisphosphonate, an anti-ulcer agent, anacid component, an alkaline effervescing component, and optionally asweetener, a flavorant, or a solubilizing agent.

[0017] In yet another aspect, the present invention provides aneffervescent composition that comprises a microencapsulatedbisphosphonate, an acid component, an alkaline effervescing component,and optionally an anti-ulcer agent.

[0018] The present invention also provides a method of inhibiting boneresorption in a mammal. The method comprises combining a boneresorption-inhibiting amount of an effervescing composition according toany aspect of the invention with water to form at least a partialsolution, and administering the solution to the mammal orally.

[0019] In another aspect, the present invention provides a method oftreating osteoporosis in a mammal. The method comprises combining anosteoporosis-treating effective amount of an effervescing compositionaccording to any aspect of the invention with water to form at least apartial solution, and administering the solution to the mammal orally.

[0020] The administration of a bisphosphonate in an effervescentcomposition to a mammal, in accordance with the present invention,results in improved bioavailability of the bisphosphonate compared toconventional non-effervescent bisphosphonate formulations. As such, ifdesired, the present invention advantageously can allow for providing asingle effervescent composition for delivering the bisphosphonate incombination with an anti-ulcer agent. Furthermore, the bisphosphonatecan be present in quantities that are larger than those provided byconventional non-effervescent solid formulations that must be able to beswallowed whole.

[0021] The present invention may be best understood with reference tothe following detailed description of the preferred embodiments.

DETAILED DESCRIPTION OF THE INVENTION

[0022] The present invention is predicated, at least in part, on thesurprising and unexpected discovery that a buffered effervescentcomposition, comprising a bisphosphonate, an acid component, and analkaline effervescing component, and having a pH of about 3 to about 6.5when dissolved in water, exhibits improved absorption, and thus improvedbioavailability, of the bisphosphonate in the body. In this respect, itis believed that the effervescent composition provides an acid mediatingeffect on the stomach pH such that the bisphosphonate is more readilyabsorbed from the intestinal tract into the blood stream.

[0023] It has further been found that effervescent compositionscomprising both a bisphosphonate and an anti-ulcer agent further enhancethe absorption of the bisphosphonate. Pursuant to the present invention,the term “anti-ulcer agent” is defined as including H₂ antagonistsand/or proton pump inhibitors.

[0024] Thus, the effervescent composition according to the inventioncomprises a bisphosphonate in the inventive effervescent compositionand, if desired, may further comprise an anti-ulcer agent. In someembodiments, the effervescent composition comprises a microencapsulatedbisphosphonate alone or in combination with an anti-ulcer agent.

[0025] The inventive composition advantageously further provides atleast one, preferably at least two, and more preferably at least three,of the following properties: quick dissolution upon introduction intowater, pleasant taste, clear aqueous composition after dissolution, andacceptable crush resistance after tableting.

[0026] The bisphosphonate can be any suitable bisphosphonate. Forexample, the bisphosphonate can be(4-amino-1-hydroxybutylidene)bisphosphonate (alendronate),[(cycloheptylamino)methylene]bisphosphonate (cimadronate),(dichloromethylene)bisphosphonate (clodronate),[1-hydroxy-3-(1-pyrrolidinyl)-propylidene]bisphosphonate (EB-1053),(1-hydroxyethylidene)bisphosphonate (etidronate),[1-hydroxy-3-(methylpentylamino)propylidene]bisphosphonate(ibandronate), (6-amino-1-hydroxyhexylidene)bisphosphonate(neridronate), [3-(dimethylamino)-1-hydroxypropylidene]bisphosphonate(olpadronate), (3-amino-1-hydroxypropylidene)bisphosphonate(pamidronate), [1-hydroxy-2-(3-pyridinyl)ethylidene]bisphosphonate(risedronate), [[(4-chlorophenyl)thio]methylene] bisphosphonate(tiludronate),[1-hydroxy-2-(imidazo-(1,2a)pyridin-3-yl)ethylidene]bisphosphonate (YH529), [1-hydroxy-2-(1H-imidazol-1-yl)ethylidene]bisphosphonate(zoledronate), or a combination thereof. Preferably, the bisphosphonateis selected from the group consisting of etidronate, risedronate,alendronate, and combinations thereof. More preferably, thebisphosphonate is alendronate or etidronate.

[0027] The effervescent composition can comprise any suitable amount ofthe bisphosphonate in order to produce an effective blood level of thebisphosphonate in the mammal (e.g., a human) to which the bisphosphonateis administered. Typically, about 0.1% or more (e.g., about 0.25% ormore or about 1% or more) bisphosphonate, based on the total weight ofthe composition, is present in the effervescent composition. Forexample, the effervescent composition can comprise about 0.25% to about33.3% bisphosphonate, based on the total weight of the composition. Insome embodiments, about 1.5% or more (e.g., about 3% or more or about 5%or more) and about 30% or less (e.g., about 20% or less) bisphosphonate,based on the total weight of the composition, is present in theeffervescent composition. The effervescent composition can beadministered to a mammal following a continuous dosing schedule. Thecontinuous schedule can be daily, once weekly, twice weekly, thriceweekly, biweekly, monthly, or every other month.

[0028] The actual amount of bisphosphonate present in the effervescentcomposition depends at least in part on the specific bisphosphonate andthe dosing schedule chosen. When the bisphosphonate is alendronate,typically about 1 mg or more and about 500 mg or less bisphosphonate ispresent, preferably about 5 mg to about 200 mg. When the bisphosphonateis risedronate, typically about 1 mg or more and about 200 mg or lessbisphosphonate is present, preferably about 2 mg to about 50 mg. Whenthe bisphosphonate is etidronate, typically about 70 mg or more andabout 2000 mg or less bisphosphonate is present, preferably about 100 mgto about 500 mg (e.g., about 200 mg to about 400 mg). When thebisphosphonate is tiludronate, typically about 50 mg or more and about1000 mg or less bisphosphonate is present, preferably about 100 mg toabout 500 mg. When the bisphosphonate is ibandronate, typically about0.1 mg or more and about 200 mg or less bisphosphonate is present,preferably about 1 mg to about 50 mg.

[0029] Moreover, if the absorption of the active agents into the bloodstream is improved (e.g., by 3 times, 5 times, or even 10 times) throughthe use of the effervescent composition of the invention versus atraditional tablet or capsule formulation containing the same amount ofthe active agent, the amount of the active agent present in theeffervescent composition can be reduced from the amount required intablet or capsule formulations (e.g., the amounts set forth above).Thus, the effervescent composition of the invention optionally maycontain only 35 wt. % or less (e.g., about 25 wt. %, or even about 15wt. % or less) than the amount by weight of active agent required intraditional tablet or capsule formulations without changing the amountof the active agent present in the bloodstream of the mammal. Theability to reduce the amount of active bisphosphonate a dosage formwithout reducing the amount absorbed into the bloodstream of the mammalis a significant step towards reducing the overall cost of the dosageform.

[0030] For example, when the bisphosphonate is administered weekly,twice weekly, biweekly, monthly or every other month, preferably theamount of bisphosphonate present in the effervescent composition is lessthan that required for tablet formulations for similar dosage schedules.When the bisphosphonate is alendronate, typically the weekly dosage isonly about 8 mg to about 16 mg, preferably about 10 mg to about 15 mg.The monthly dosage of alendronate typically is about 30 mg to about 200mg, preferably about 50 mg to about 120 mg. The dosage for every othermonth administration of alendronate typically is about 50 mg to about500 mg, preferably about 100 mg to about 300 mg. When the bisphosphonateis etidronate, the monthly dosage typically is about 400 mg to about 800mg, preferably about 500 mg to about 700 mg. The dosage for every othermonth administration of etidronate typically is about 800 mg to about1600 mg, preferably about 1000 mg to about 1500 mg. When thebisphosphonate is ibandronate, the monthly dosage typically is about 50mg to about 90 mg, preferably about 60 mg to about 85 mg. The dosage forevery other month administration of ibandronate typically is about 100mg to about 300 mg, preferably about 125 mg to about 250 mg. When thebisphosphonate is residronate, the monthly dosage typically is about 20mg to about 140 mg, preferably about 50 mg to about 100 mg. The dosagefor every other month administration of etidronate typically is about100 mg to about 300 mg, preferably about 120 mg to about 200 mg.

[0031] Currently approved dosage regimens for alendronate include 5 mgor 10 mg once daily and 35 mg or 70 mg once weekly for treatment ofosteoporosis. For treatment of Paget's disease, the recommended dosageregimen is 40 mg once daily. Currently approved dosage regimens forrisedronate include 5 mg once daily and 35 mg once weekly for treatmentof osteoporosis. Currently approved dosage regimens for etidronateinclude 400 mg once daily (5-20 mg/kg/day) over six months for treatmentof Paget's disease. Currently approved dosage regimens for tiludronateinclude 400 mg once daily over 3 months for treatment of Paget'sdisease. All dosage amounts stated herein are in terms of the freebisphosphonic acid.

[0032] The bisphosphonate can be finely milled to enhance the absorptionof the bisphosphonate. In this respect, such finely milled particles ofthe bisphosphonate result in more surface area being exposed to theabsorption medium, thereby maximizing absorption. Desirably, thebisphosphonate is milled to a particle size of about 100 microns or less(e.g., about 4 microns to about 100 microns). Preferably, thebisphosphonate is milled to a particle size of about 5 microns to about70 microns (e.g., about 10 microns to about 50 microns).

[0033] The acid component can be any suitable acid component. Typically,the acid component is an organic or mineral acid that is safe forconsumption and which provides for effective and rapid effervescentdisintegration upon contact with water and the alkaline effervescentcomponent. For example, the acid component can be selected from thegroup consisting of citric acid, tartaric acid, malic acid, fumaricacid, adipic acid, succinic acid, acid anhydrides, acid salts (e.g.,sodium salts and potassium salts), mixtures of acid salts; acid salts ofdisodium dihydrogen pyrophosphate, acid citrate salts (e.g., monosodiumcitrate and disodium citrate) and other related organic acids and theirsalts, and combinations thereof. Preferably, the acid componentcomprises citric acid (e.g., citric acid anhydrous) and optionally anyof the other acid components described above (e.g., an organic acid orsalt, preferably monosodium citrate and/or monopotassium citrate). Theuse of non-sodium acid components is desirable for use with patientsrequiring electrolyte maintenance, e.g., hypertensive and other cardiacpatients.

[0034] The alkaline effervescing component can be any suitable alkalineeffervescent component. Typically, the alkaline effervescing componentis an organic or mineral based (e.g., alkali metal carbonate) that issafe for consumption and provides effective and rapid effervescentdisintegration upon contact with water and the acid component. Forexample, the alkaline effervescing component can be selected from thegroup consisting of carbonate salts, bicarbonate salts, and mixturesthereof. Preferably, the alkaline effervescing component is selectedfrom the group consisting of sodium bicarbonate, sodium carbonateanhydrous, potassium carbonate, and potassium bicarbonate, sodiumglycine carbonate, calcium carbonate, calcium bicarbonate, L-lysinecarbonate, arginine carbonate, and combinations thereof. In someembodiments, the alkaline effervescing component is sodium bicarbonate,potassium bicarbonate, sodium carbonate, or a combination thereof.

[0035] More preferably, the alkaline effervescing component comprises acarbonate salt, a bicarbonate salt, and optionally another suitablealkaline effervescing components as described above. The carbonate saltcan be any suitable carbonate salt and typically is selected from thegroup consisting of sodium carbonate, potassium carbonate, andcombinations thereof. The bicarbonate salt can be any suitablebicarbonate salt and typically is selected from the group consisting ofsodium bicarbonate, potassium bicarbonate, and combinations thereof. Theuse of non-sodium alkaline effervescing components is desirable for usewith patients requiring electrolyte maintenance, e.g., hypertensive andother cardiac patients.

[0036] The acid component and the alkaline effervescent component can bepresent in the effervescent composition in any suitable amount. Therelative amounts of acid component and alkaline effervescent componentare such that the effervescent composition, when dissolved in water,produces a buffer solution. For the purposes of clarity, by the phrase“effervescent composition completely dissolves” it is meant that theacid component and the alkaline effervescent component are completelydissolved in the water, even though another components (e.g., thebisphosphonate or a microencapsulated bisphosphonate) are not completelydissolved or not at all dissolved. The buffer solution is produced whenthe acid component reacts with the alkaline effervescent component toproduce a solution containing the acid component and/or the alkalineeffervescent component in equilibrium with the fully deprotonated saltof the acid component. For example, when the acid component is citricacid and the alkaline component is sodium bicarbonate, the buffer wouldconsist of an acid form of citric acid and sodium citrate (e.g., thefully deprotonated salt of citric acid). Typically, the bufferedsolution has a pH of about 3 to about 6.5 (e.g., about 3.5 to about 6.5or about 4 to about 6.5). Preferably, the buffered solution has a pH ofabout 3.5 to about 6 (e.g., about 4 to about 6). More preferably, thebuffered solution has a pH of about 4 to about 5.5 (e.g., 4.5 to about5.5). For example, in some embodiments the buffered solution contains anamount of fully deprotonated salt of the acid component that is at leastabout 1.5 times (e.g., at least about 1.75 times or at least about 2times) the amount of acid equivalents (e.g., equivalents of acid groupswithin the acid component). In some embodiments, the amount of acidequivalents is non-zero.

[0037] Desirably, the acid component is present in the effervescentcomposition in an amount of about 25% to about 75% based on the totalweight of the composition and the alkaline effervescing component ispresent in the effervescent composition in an amount of from about 20%to about 60% based on the total weight of the composition. In apreferred embodiment, the amount of citric acid may be less than about20% (e.g., about 1% to about 15%, or about 5% to about 10%) based on thetotal weight of the acid component and the alkaline effervescingcomponent. The amount of carbonate salt may be less than about 20%(e.g., about 0.1% to about 10%, or about 1% to about 7%) based on thetotal weight of the acid component and the alkaline effervescingcomponent. The amount of bicarbonate salt may be less than about 60%(e.g., about 25% to about 50%, or about 30% to about 45%) based on thetotal weight of the acid component and the alkaline effervescingcomponent.

[0038] Preferably, the weight ratio of bicarbonate to carbonate saltshould be controlled to provide optional performance of the effervescentformulation. In this regard, it is advantageous that the amount ofbicarbonate salt may be at least about 4 times (e.g., preferably atleast about 6 times, or more preferably at least about 8 times) theamount by weight of carbonate salt. In an especially preferredembodiment, the effervescent composition comprises about 1% to about 15%citric acid, about 35% to about 60% monosodium citrate, about 0.1% toabout 10% carbonate salt, and about 25% to about 50% bicarbonate salt,based on the total weight of the acid component and the alkalineeffervescing component.

[0039] Advantageously, the inventive effervescent composition maycomprise a bisphosphonate, an acid component comprising about 1% toabout 15% citric acid by weight based on the total weight of the acidcomponent and the alkaline effervescing component, and an alkalineeffervescing component comprising about 0.1% to about 10% by weightcarbonate salt and about 25% to about 50% by weight bicarbonate saltbased on the total weight of the acid component and the alkalineeffervescing component, the effervescent composition, when dissolved inwater, providing an aqueous composition having a buffered pH of about 3to about 6.5 (e.g., about 4 to about 6.5, or about 5 to about 6.5). Sucha composition may preferably further include the weight ratios ofbicarbonate salt to carbonate salt described above.

[0040] Desirably, administration of the buffer solution produced upondissolution of the effervescent composition in water to a mammal (e.g.,a patient) produces a stomach pH in the mammal of at least about 3 orgreater (e.g., about 3.5 or greater), more preferably about 4 or greater(e.g., about 4.5 or greater). The buffer solution typically is capableof mediating the pH of a patient's stomach for at least about 10 minutesor more (e.g., about 15 minutes or more). In some embodiments, thebuffer solution is capable of mediating the pH of a patient's stomachfor up to about 30 minutes or more (e.g., up to about 45 minutes ormore).

[0041] In one embodiment, the effervescent composition optionallyfurther comprises an anti-ulcer agent. The anti-ulcer agent can be anH₂-antagonist, a proton pump inhibitor, or a combination thereof. TheH₂-antagonist can be any suitable H₂-antagonist. For example, theH₂-antagonist can be ranitidine, cimetidine, famotidine, nizatidine, ora combination thereof. Preferably, the H₂-antagonist is ranitidine orcimetidine. Typically, the H₂-antagonist is present in the effervescentcomposition in an amount of about 3.3% to about 57.5% (e.g., about 8% toabout 40%) based on the total weight of the composition. TheH₂-antagonist preferably is present in the effervescing composition inan amount of about 5 mg to about 500 mg, depending on the specificantagonist selected. By way of about 300 mg (e.g., about 50 mg to about200 mg) H₂-antagonist; when the H₂-antagonist is cimetidine, thecomposition comprises about 25 mg to about 400 mg (e.g., about 50 mg toabout 350 mg) H₂-antagonist; when the H₂-antagonist is famotidine, thecomposition comprises about 2 mg to about 50 mg (e.g., about 5 mg toabout 30 mg) H₂-antagonist; and when the H₂-antagonist is nizatidine,the composition comprises about 25 mg to about 350 mg (e.g., about 50 toabout 300 mg) H₂-antagonist.

[0042] The anti-ulcer agent comprises any suitable proton pumpinhibitor. By way of example, the proton pump inhibitor can beomeprazole, lansoprozole, rabeprazole, pantoprazole, or a combinationthereof. Preferably, the proton pump inhibitor is omeprazole. Typically,the proton pump inhibitor is present in an amount of from about 0.5% toabout 60% by weight of the composition (e.g., about 5% to about 40%).The proton pump inhibitor is present in the effervescing composition inan amount of about 5 mg to about 100 mg, depending on the specificproton pump inhibitor used. For example, when the proton pump inhibitoris omeprazole, the composition comprises about 10 mg to about 30 mgproton pump inhibitor; when the proton pump inhibitor is lansoprazole,the composition comprises about 2 mg to about 30 mg (e.g., about 5 mg toabout 20 mg) proton pump inhibitor; when the proton pump inhibitor israbeprazole, the composition comprises about 5 mg to about 60 mg (e.g.,about 10 to about 45 mg) proton pump inhibitor; and when the proton pumpinhibitor is pantoprazole, the composition comprises about 5 mg to about50 mg (e.g., about 10 mg to about 35 mg) proton pump inhibitor.

[0043] When the effervescent composition comprises one of the anti-ulceragents described above, the capacity of the buffer solution to mediatethe pH of a patient's stomach typically is extended beyond that of theeffervescent composition without the anti-ulcer agent. For example, thedissolved solution is able to mediate the pH of a patient's stomach forup to about 60 minutes or more (e.g., up to about 90 minutes or more orup to about 120 minutes or more).

[0044] The effervescent composition of the invention desirably has apleasing taste. The taste of a pharmaceutical composition is importantas it enhances the willingness of patients to utilize the dosage form.Many active agents, such as bisphosphonates and anti-ulcer agents, havean objectionable taste that must be masked by the formulation in whichthe active agents are delivered. Therefore, the effervescent compositionpreferably comprises a sweetener, a flavorant, or a combination thereof.It was also found that the effect of the latter is enhanced relative toknown effervescent compositions due to the inventive nature of thepresent effervescent composition. In some embodiments, the effervescentcomposition comprises both a sweetener and a flavorant.

[0045] The sweetener can be any suitable natural or artificial sweeteneror a combination of natural and artificial sweeteners. Acceptablenatural sweeteners include members selected from the group of glucose,dextrose, invert sugar, fructose, glycyrrhizic acid, and mixturesthereof. Typically, the natural sweetener is present in the effervescentcomposition in an amount of about 10% to about 50% (e.g., about 20% toabout 40%) based on the weight of the composition. Acceptable artificialsweeteners include members selected from the group consisting ofsaccharin; aspartame; chloro-derivatives of sucrose such as sucralose,cyclamate, acesulfame-K; sugar alcohols such as sorbitol, mannitol, andxylitol; and mixtures thereof. Typically, the artificial sweetener ispresent in the effervescent composition in an amount of about 0 to about5% (e.g., about 0.1 to about 2.5%) based on the weight of thecomposition. Preferably, the sweetener is an artificial sweetenerselected from the group consisting of aspartame, saccharin,acesulfame-K, xylitol, Splenda®, and combinations thereof. The effectiveconcentration of a sweetener is determined by the strength of itssweetness, solubility, and masking ability for a specific activeingredient(s). For example, when the sweetener is aspartame, about 10 mgto about 50 mg aspartame is present in the effervescent composition.When the sweetener is saccharin, about 10 mg to about 30 mg saccharin ispresent in the effervescent composition. When the sweetener isacesulfame-K, about 10 mg to about 50 mg acesulfame-K is present in theeffervescent composition. When the sweetener is xylitol, about 100 mg toabout 400 mg xylitol is present in the effervescent composition. Whenthe sweetener is Splenda®, about 10 mg to about 50 mg Splenda® ispresent in the effervescent composition.

[0046] The flavorant can be a natural or synthetic flavorant. Typically,the flavorant is present in the effervescent composition in an amount ofabout 0% to about 10% (e.g., about 1% to about 7.5%) based on the weightof the composition. Acceptable flavorants include members selected fromthe group consisting of volatile oils, synthetic flavor oils,oleoresins, plant extracts (e.g., green tea flavor), and combinationsthereof. Desirable flavorants include a member selected from the groupconsisting of citrus oils such as lemon, orange, grape, lime andgrapefruit; fruit essences such as apple, pear, peach, grape,strawberry, raspberry, cherry, plum, pineapple, and apricot; and otherfruit flavors. Other useful flavorants include aldehydes and esters suchas benzaldehyde (cherry, almond), citral (lemon, lime), neral (lemon,lime), decanal (orange, lemon), C₈-aldehyde (citrus fruits), C₉-aldehyde(citrus fruits), C₁₂-aldehyde (citrus fruits), tolylaldehyde (cherry,almond), 2,6-dimethyloctanal (green fruit), and 2-dodecenal (citrus,mandarin), and mixtures thereof. Preferably, the flavorant is cherry,citrus, or orange. The flavorant typically is present in theeffervescent composition in an amount of about 10 mg to about 100 mg.

[0047] The pH range of the buffered aqueous composition resulting fromdissolution of the effervescent composition is desirably in the range ofabout 3 to about 6.5 (e.g., about 4 to about 6.5, or about 5 to about6.5). In order to avoid decomposition of many acid-sensitive activeagents, it is necessary to remain at a pH above the pKa of the activeagent, preferably a pH that is at least 0.7 pH units above the pKa, oreven 1 pH unit above the pKa of the active agent. For example, when theeffervescent composition comprises an anti-ulcer agent, such asomeprazole, it is desirable to remain at a pH above the pKa of theanti-ulcer agent. The pKa of omeprazole is about 3.9, thus aneffervescent composition of the invention comprising omeprazoledesirably has a buffered pH of at least about 5. The upper limit for thebuffer pH is ultimately limited by the tolerance of the stomach liningfor alkaline solutions. Typically the upper limit of the stomachtolerance is about 10. However, the upper pH limit may further belimited by the pH tolerance of the ingredients included in theeffervescent formulation. For example, the perceived flavor of aflavorant or sweetener can be affected by the pH of the bufferedsolution. Many flavorants undergo a chemical change causing theflavorants to lose or change their flavor at alkaline pH values (e.g.,at pH values of about 7 or higher, or about 7.5 or higher). Thus, it hasbeen found that selection of an appropriate buffered pH range for theeffervescent composition of the invention requires a delicate balance ofthe pH considerations of the active agent (e.g., bioavailability andstability), as well as the considerations of the stomach tolerance andstability of inactive ingredients such as flavorants and sweeteners thatare responsible for taste-masking.

[0048] The effervescent composition optionally further comprises asolubilizing agent, which aids in the transition of the bisphosphonatefrom the gastrointestinal tract to the blood by solubilizing thebisphosphonate and facilitating its transfer into the mucosal interfaceof the gastrointestinal tract. The solubilizing agent can be anysuitable solubilizing agent. For example, the solubilizing agent can bea polyvinylpyrrolidone, a polyethylene glycol, a dextran, or acombination thereof. The polyvinylpyrrolidone and polyethylene glycolcan have any suitable molecular weight. For example, thepolyvinylpyrrolidone can have a molecular weight of about 20,000 g/molto about 40,000 g/mol, preferably about 25,000 g/mol to about 35,000g/mol, more preferably about 28,000 g/mol to about 32,000 g/mol. Thepolyethylene glycol can have a molecular weight of about 2000 g/mol toabout 10,000 g/mol (e.g., about 4000 g/mol, about 6000 g/mol, or about8000 g/mol). The dextran can be any suitable branched poly-D-glucosidehaving predominantly C₁-₆ glycosidic bonds. In some embodiments, thesolubilizing agent comprises both polyvinylpyrrolidone and polyethyleneglycol. Typically, the solubilizing agent is present in the effervescentcomposition in an amount of from about 0.1% or more based on the weightof the composition. For example, about 0.1% to about 10% (e.g., about 1%to about 5%) based on the weight of the composition polyvinylpyrrolidoneand/or about 20 mg to about 100 mg polyethylene glycol can be present inthe effervescent composition. When the solubilizing agent is a dextran,about 1% to about 20%, preferably about 5% to about 15% (e.g., about10%) dextran based on the weight of the composition can be present inthe effervescent composition.

[0049] In one embodiment, the effervescent composition comprises abisphosphonate, an anti-ulcer agent, an acid component, an alkalineeffervescing component, and, optionally, one or more ingredientsselected from sweeteners, flavorants, and solubilizing agents.Typically, the effervescent composition comprises about 0.1% to about19% bisphosphonate, about 0.5% to about 50% anti-ulcer agent, about 15%to about 60% acid component, about 20% to about 70% alkalineeffervescing component, about 0% to about 5% sweetener, about 0% toabout 10% flavorant, and about 0% to about 10% solubilizing agent.Preferably, the effervescent composition comprises about 0.5% to about10% bisphosphonate, about 2% to about 30% anti-ulcer agent, about 25% toabout 45% acid component, about 30% to about 60% alkaline effervescingcomponent, about 2% to about 4% sweetener, about 3% to about 8%flavorant, and about 1% to about 5% solubilizing agent. The percentamounts recited above are based on the total weight of the effervescentcomposition.

[0050] In another embodiment, the effervescent composition comprises abisphosphonate compound that is encapsulated (e.g., microencapsulated)in a time-release (e.g., sustained-, delayed- or directed-release)delivery system. The encapsulation of the bisphosphonate is preferredwhen delayed release of the active ingredient into the stomach isdesired, for example, when the bisphosphonate is administeredsimultaneously with an H₂-antagonist or a proton pump inhibitor.Encapsulation of the bisphosphonate could minimize or eliminateirritation of the esophagus of the patient and other patient distresssuch as nausea. Encapsulation of the bisphosphonate also could delayrelease of the bisphosphonate until the stomach absorbs the anti-ulceragent and inhibition of the stomach's acid production has begun. Theencapsulation could delay release of the bisphosphonate by about 2 toabout 30 minutes, preferably by about 5 to about 10 minutes. It is to benoted that effervescent compositions comprising encapsulatedbisphosphonate, when dissolved in water, achieve the desired buffered pHin accordance with the invention. In this respect, the acid componentand the alkaline effervescent component are completely dissolved but, ofcourse, the encapsulated bisphosphonate remains encapsulated.

[0051] The bisphosphonate can be encapsulated in any suitable manner aswill be readily appreciated by one of ordinary skill in the art. Forexample, the polymer coating can be any suitable differentiallydegrading coating including microencapsulation, enteric coating,multiple coating, and the like. The polymer coating may be one thatresists disintegration upon contact with the saliva but instantlyreleases the bisphosphonate upon contact with gastric juice in thestomach. Alternatively, the polymer coating may be one that resistsrapid disintegration in the presence of gastric juice. Suitable coatingpolymers include biodegradable polymers such as polylactic acid,polyglycolic acid, copolymers of lactic and glycolic acid,polyorthoesters, and polyanhydrides thereof. The bisphosphonate also canbe encapsulated by a polymer coating such as a cellulosic (e.g., methylor ethyl cellulose) coating, a wax coating, a gum coating, or within aliposomal delivery system. Suitable methods of preparing effervescentcompositions containing microencapsulated active ingredients aredescribed, for example, in U.S. Pat. Nos. 4,462,982, 4,710,384,5,178,878, and 5,709,886. Preferably, the microencapsulatedbisphosphonate has a mean particle size of about 25 microns to about 120microns (e.g., about 40 microns to about 70 microns). More preferably,the microencapsulated bisphosphonate has a mean particle size of about50 microns.

[0052] The effervescent compositions described above optionally furthercomprise a colorant. The colorant can be any suitable colorant includingnatural colorants, food, drug and cosmetics (FD&C) colorants, and drugand cosmetic (D&C) colorants. Suitable natural colorants include redbeet powder and beta-carotene powder.

[0053] The effervescent compositions described above optionally furthercomprise other ingredients to aid in the formulation of the compositionand/or for aesthetic purposes. Such other ingredients include, forexample, fragrances, dyes, fillers such as calcium sulfate, starch, andbinders. Desirable binders assist in tablet compression and can includestarches, pregelatinized starches, gelatin, methylcellulose, sodiumcarboxymethylcellulose, ethylcellulose, polyacrylamides,polyvinyloxoazolidone, polyvinylalcohols, and polyvinylpyrrolidone.

[0054] The effervescent compositions described above optionally furthercomprise a disintegrant to enhance the disintegration of the compressedtablet in water. The disintegrant can be any suitable disintegrant. Forexample, the disintegrant can be starch, alginic acid, guar gum, kaolin,bentonite, sodium starch glycolate, isoamorphous silicate, andmicrocrystalline cellulose.

[0055] The effervescent compositions described above optionally furthercomprise a lubricant, which is applied to dies before the granularmixture is compressed into the effervescent tablet. Lubricants caninclude hydrogenated or partially hydrogenated vegetable oils such ascorn oil, canola oil, cottonseed oil, sesame oil, soybean oil, grapeseed oil, sunflower oil, safflower oil, olive oil, peanut oil, andcombinations thereof. Lubricants can also include calcium stearate,magnesium stearate, zinc stearate, polyoxyethylene monostearate, talc,polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, magnesiumlauryl sulfate, light mineral oil, and combination thereof. Lubricantscan form a hydrophobic coating on an effervescent tablet and affect thedissolution rate of the tablet. The preferred embodiment of theinvention uses paraffin oil or magnesium stearate as a lubricant.Paraffin oil or magnesium stearate dust imparts desirable dissolutioncharacteristics to the tablets and facilitates the high-speed productionof the tablets.

[0056] The effervescent compositions described above can be formulatedas a tablet, granulate, or a powder. Suitable methods for producing theeffervescent compositions of the invention include those described inU.S. Pat. Nos. 4,687,662, 4,942,039, 5,348,745, 5,415,870, 5,480,652,5,853,759, and 6,284,272. Preferably, the acid component and thealkaline effervescing component are at least partially reacted with eachother during granulation with the bisphosphonate.

[0057] Typically the effervescent compositions of the invention have atotal weight of about 1500 mg or more (e.g., about 2000 mg or more). Insome embodiments, the effervescent composition has a total weight ofabout 2500 mg or more. Preferably, effervescent compositions have atotal weight of about 2000 mg to about 6000 mg (e.g., about 3500 mg toabout 5000 mg).

[0058] The effervescent composition of the invention, when formulated asa tablet, desirably has a disintegration time of about 180 s or less(e.g., advantageously about 150 s or less, or preferably about 120 s orless) upon contact with about 60 ml of water. More preferably, thedisintegration time of the effervescent tablet is about 90 s or less,and most preferably about 60 s or less. The disintegration time depends,at least in part, on the relative amounts of the “fast-reactingcomponents” to the “slow-reacting components.” Citric acid and carbonatesalts react very fast with alkaline compounds and acid compounds,respectively, upon dissolution in water. Other effervescent componentslike monosodium citrate and bicarbonate salts react a bit slower withalkaline compounds and acid compounds, respectively, upon dissolution inwater. It has been discovered that by balancing the relative amounts ofthe fast-reacting compounds to the slow-reacting compounds, aneffervescent composition can be produced which has a fast disintegrationtime and, preferably also provides a clear solution that issubstantially free or totally free of un-dissolved acid or alkalineeffervescent components. Clear solutions are more aesthetically pleasingto patients than solutions containing suspended particles that can beseen by the naked eye.

[0059] The effervescent composition of the invention typically has anacid neutralizing capacity (ANC) of about 10 mEq or more of HCl.Preferably, the effervescent composition of the invention typically hasan ANC of about 12 mEq or more (e.g., about 13 to about 20 mEq HCl). TheANC can be determined by inflection point titration (IPT) method or by aGran function plot method. IPT involves plotting the pH of a solution ofthe effervescent composition as a function of the volume of strong acidadded and identifying the tinflection point of the titration. The Granfunction plot method involves plotting a Gran function (e.g., the sum ofthe initial volume (V_(o)) and volume acid added (V_(i)) multiplied bythe antilog of the change in pH (i.e., [(V_(o)+V_(i))(10^(−pH)])) versusthe volume of acid added (V_(i)) and fitting a line through the datapoints (e.g., by regression analysis). The ANC value is determined bymultiplying the normality of the acid by the linear constant (i.e., thepoint at which the line crosses the x-axis), and dividing by the samplevolume.

[0060] The effervescent compositions of the invention preferably areused in a method of treating and/or preventing conditions or diseasestates in a mammal involving excessive bone resorption related to boneformation. Such disease states including osteoporosis (e.g.,post-menopausal osteoporosis, steroid-induced osteoporosis, maleosteoporosis, disease-induced osteoporosis, idiopathic osteoporosis),Paget's disease, abnormally increase bone turnover, periodontal disease,localized bone loss from periprosthetic osteolysis, and bone fractures.

[0061] In one embodiment, the effervescent compositions are used in amethod of inhibiting bone resorption in a mammal. The treatmentcomprises combining a bone resorption inhibiting amount of theeffervescent composition with water to form at least a partial solutionand administering the solution to the mammal (e.g., patient) orally.

[0062] In another embodiment, the effervescent compositions are used ina method of treating osteoporosis in a mammal. The treatment methodcomprises combining an osteoporosis-treating effective amount of theeffervescent composition with water to form at least a partial solutionand administering the solution to the mammal (e.g., patient) orally.

[0063] The administration of the effervescent composition to the mammalpreferably causes the pH of the contents of the mammal's stomach (e.g.,the gastric juices) to be raised to a pH of about 3 or greater. Morepreferably, the administration of the effervescent composition to themammal causes the pH of the mammal's stomach to be raised to a pH ofabout 3.5 or greater (e.g., about 4 or greater). Typically, the pH ofthe mammal's stomach is not raised above about 6.5 (e.g., not aboveabout 6).

[0064] The following examples further illustrate the invention but, ofcourse, should not be construed as in any way limiting its scope.

EXAMPLE 1

[0065] This example illustrates a process for preparing the effervescenttablets of the invention, comprising etidronate and an H₂-antagonist(anti-ulcer agent), using a wet granulation method.

[0066] An effervescent tablet of etidronate is formed from theingredients listed in Table 2. TABLE 2 Ingredient Amount Functionetidronate  70 to 800 mg active bisphosphonate cimetidine 100 to 400 mganti-ulcer agent citric acid 800 to 1600 mg acid component sodiumbicarbonate 800 to 1600 mg alkaline effervescing cmpd potassiumbicarbonate  0 to 800 mg alkaline effervescing cmpd sodium carbonate  20to 100 mg alkaline effervescing cmpd polyvinylpyrrolidone  1 to 5 wt.%by wt solubilizer polyethlene glycol 6000  20 to 100 mg solubilizeraspartame  10 to 50 mg sweetener raspberry flavor  10 to 100 mgflavorant

[0067] All process steps for this example are performed underapproximately 20% relative humidity. The etidronate, cimetidine,polyvinylpyrrolidone, a part of the citric acid, a part of the sodiumbicarbonate, a part of the potassium bicarbonate, a part of the sodiumcarbonate, and a part of the polyethylene glycol are homogeneously mixedin a high-speed mixer. The powders are wetted with a small amount ofwater. This wetting initiates a slight effervescent reaction between theacidic and the alkaline components. This effervescent reaction binds thecomponents together with the polyvinylpyrrolidone. The wetted powdersare dried with heat in a vacuum at a very low humidity until the powderachieves approximately 0.15% loss on drying. After sieving for particlesize the dried granulate is mixed in a tumbler with the remainingingredients.

[0068] The tablet mixture is compressed on a suitable commerciallyavailable rotary tablet press. The dies are lined with nylon insertsand/or lubricated with a thin film of paraffin oil or magnesiumstearate, which is applied by spraying. The tablets are filled on-lineinto tubes or strips.

EXAMPLE 2

[0069] This example illustrates a process for preparing the effervescenttablets of the invention, comprising etidronate and an H₂-antagonist(anti-ulcer agent), using a wet granulation method.

[0070] The ingredients listed in Table 3 are used in the production ofan effervescent tablet of the invention. TABLE 3 Actual AmountIngredient Amount Range (in mg) (in mg) etidronate  70-800 200cimetidine 100-400 250 citric acid  800-1600 1400  sodium bicarbonate 800-1600 800 potassium bicarbonate  0-800 695 sodium carbonate  20-200160 polyvinylpyrrolidone 1-5 wt.% 2 wt. % aspartame 10-50 20 saccharin10-30 20 polyethylene glycol 6000  20-100 60 flavorant  10-100 25colorant  0-10  5

[0071] The etidronate, polyvinylpyrrolidone, and sodium bicarbonate arepremixed. The colorant, cimetidine, and sodium carbonate are premixed.Place the citric acid in a bowl of a suitable blender. Add a sufficientamount of water to the citric acid slowly and mix thoroughly to form amoist blend. Add to the blend, in sequence, while mixing, the sodiumbicarbonate mix and the sodium carbonate mix until uniformlydistributed. While mixing, the polyethylene glycol is added and themixture is blended until uniformly distributed.

[0072] The tablet mixture is compressed on a suitable commerciallyavailable rotary tablet press. The dies are lined with nylon insertsand/or lubricated with a thin film of paraffin oil or magnesiumstearate, which is applied by spraying. The tablets are filled on-lineinto tubes or strips.

EXAMPLE 3

[0073] This example illustrates a process for preparing the effervescenttablets of the invention, comprising etidronate and an proton pumpinhibitor (anti-ulcer agent), using a wet granulation method.

[0074] The ingredients listed in Table 4 are used in the production ofan effervescent tablet of the invention. TABLE 4 Ingredient ActualAmount (in mg) etidronate 200 omeprazole 20 citric acid 420 sodiumcitrate monobasic 1820 potassium-sodium tartrate 5 sodium bicarbonate800 potassium bicarbonate 695 sodium carbonate 160 polyvinylpyrrolidone2 wt. % aspartame 30 polyethylene glycol 8000 45 flavorant 50 colorant 5

[0075] Blend etidronate, omeprazole, citric acid, sodium citratemonobasic, potassium sodium tartrate, polyvinylpyrrolidone, polyethyleneglycol, and aspartame in a suitable blender. Quickly add all of waterand mix until a workable mass is formed. Granulate through a suitablescreen using a granulator. Spread evenly on a paper-lined tray or afluid bed dryer. Place a dried granulation in a suitable blender and addpowder sodium bicarbonate, potassium bicarbonate, and sodium carbonate.Mix well. Add flavorant and colorant and mix until uniformlydistributed.

[0076] The tablet mixture is compressed on a suitable commerciallyavailable rotary tablet press. The process is carried out at roomtemperature and with a relative humidity not higher than 15-20%. Thedies are lined with nylon inserts and/or lubricated with a thin film ofparaffin oil or magnesium stearate, which is applied by spraying. Thetablets are filled on-line into tubes or strips.

[0077] The tablet when dissolved in 120 ml water produces a solutionhaving a buffered pH of about 5.5 to about 6.0.

EXAMPLE 4

[0078] This example illustrates a process for preparing the effervescenttablets of the invention, comprising etidronate and an H₂-antagonist(anti-ulcer agent), using a dry granulation method.

[0079] The ingredients listed in Table 5 are used in the production ofan effervescent tablet of the invention. TABLE 5 Ingredient ActualAmount (in mg) etidronate 200 ranitidine 200 citric acid 525 sodiumcitrate monobasic 1820 Potassium-sodium tartrate 5 Sodium bicarbonate800 potassium bicarbonate 695 sodium carbonate 40 polyvinylpyrrolidone 2wt. % Splenda ® 30 polyethylene glycol 8000 45 flavorant 50 colorant 5

[0080] Etidronate, ranitidine, polyethylene glycol, andpolyvinylpyrrolidone are blended in a suitable mixer until uniform. Tothe mixture are added citric acid, potassium sodium tartrate, and sodiumcitrate monobasic, alternating with sodium bicarbonate, potassiumbicarbonate, and sodium carbonate. After all the acidic and alkalinecomponents are added, add the remaining ingredients and mix untiluniform. Roller compact the powder mix followed by granulation using asuitable screen.

[0081] The tablet mixture is compressed on a suitable commerciallyavailable rotary tablet press. The process is carried out at roomtemperature and with a relative humidity not higher than 15-20%. Thedies are lined with nylon inserts and/or lubricated with a thin film ofparaffin oil or magnesium stearate, which is applied by spraying. Thetablets are filled on-line into tubes or strips.

[0082] The tablet when dissolved in 120 ml water produces a solutionhaving a buffered pH of about 3.0 to about 3.4.

EXAMPLE 5

[0083] This example illustrates a process for preparing the effervescenttablets of the invention, comprising etidronate and a proton pumpinhibitor (anti-ulcer agent), using a two-part dry granulation method.

[0084] The ingredients listed in Table 6 are used in the production ofan effervescent tablet of the invention. TABLE 6 Ingredient ActualAmount (in mg) Etidronate 200 Lansoprazole 15 citric acid 475 sodiumcitrate monobasic 1820 potassium sodium tartrate 5 sodium bicarbonate800 potassium bicarbonate 695 sodium carbonate 80 Polyvinylpyrrolidone 2wt. % Xylitol 200 polyethylene glycol 8000 45 Flavorant 50 Colorant 5

[0085] In a first mixer, etidronate, lansoprazole, part of the sodiumbicarbonate, part of the potassium bicarbonate, polyethylene glycol, andpolyvinylpyrrolidone are blended and then the mixture is rollercompacted. In a second mixer, citric acid, sodium citrate monobasic,potassium sodium tartrate, the remaining sodium bicarbonate andpotassium bicarbonate, sodium carbonate, colorant, flavorant, andxylitol are blended and then roller compacted. The mixtures from thefirst and second mixer are then granulated through a suitable screen.The remaining ingredients are added and the mixture is blended untiluniform.

[0086] The tablet mixture is compressed on a suitable commerciallyavailable rotary tablet press. The process is carried out at roomtemperature and with a relative humidity not higher than 15-20%. Thedies are lined with nylon inserts and/or lubricated with a thin film ofparaffin oil or magnesium stearate, which is applied by spraying. Thetablets are filled on-line into tubes or strips.

[0087] The tablet when dissolved in 120 ml water produces a solutionhaving a buffered pH of about 4.0 to about 4.4.

EXAMPLE 6

[0088] This example demonstrates that the bioavailability of etidronatefrom effervescent tablets is greater than that obtained withnon-effervescent etidronate tablets.

[0089] A group of 6 beagle dogs is dosed with etridronate following arandom three-way design with a two-week washout between each treatmentphase. In the first treatment phase (control), the beagle dogs areadministered Didronel® (etidronate) tablets (200 mg). In the second andthird treatment phases, the beagle dogs are administered effervescenttablets of the invention containing 200 mg etidronate active ingredientin either a buffered or unbuffered formulation, respectively.

[0090] For each treatment phase, the bioavailability of etidronate inthe beagle dogs is determined. Urine samples are collected after 24 and48 hours and the concentration of etidronate for each sample isdetermined by chromatographic analysis. The amount of etidronate foundin the urine reflects the percentage of etidronate that was absorbed bythe body but did not bind to the surface of the bone. While the amountof etidronate absorbed by the body is dependent on the mode ofadministration, the percentage of the absorbed etidronate that becomesbound to the bone surface is independent of the mode of drugadministration. Thus, an increase in the amount of etidronate in theurine is reflective of an overall increase in absorption.

[0091] For the first treatment phase group of beagle dogs (control), theamount of etidronate absorbed into the body is expected to be about 3%.For the second and third treatment phase group (invention), the amountof etidronate absorbed into the body is expected to be about 6% to about10%. Thus, the bioavailibility of etidronate in treatment phase groups 2and 3 is expected to at least 50% greater than the bioavailibility fromconventional tablet formulations administered to treatment phase group1.

[0092] All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

[0093] The use of the terms “a” and “an” and “the” and similar referentsin the context of describing the invention (especially in the context ofthe following claims) are to be construed to cover both the singular andthe plural, unless otherwise indicated herein or clearly contradicted bycontext. Recitation of ranges of values herein are merely intended toserve as a shorthand method of referring individually to each separatevalue falling within the range, unless otherwise indicated herein, andeach separate value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein, isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention unless otherwise claimed. Nolanguage in the specification should be construed as indicating anynon-claimed element as essential to the practice of the invention.

[0094] Preferred embodiments of this invention are described herein,including the best mode known to the inventors for carrying out theinvention. Of course, variations of those preferred embodiments willbecome apparent to those of ordinary skill in the art upon reading theforegoing description. The inventors expect skilled artisans to employsuch variations as appropriate, and the inventors intend for theinvention to be practiced otherwise than as specifically describedherein. Accordingly, this invention includes all modifications andequivalents of the subject matter recited in the claims appended heretoas permitted by applicable law. Moreover, any combination of theabove-described elements in all possible variations thereof isencompassed by the invention unless otherwise indicated herein orotherwise clearly contradicted by context.

What is claimed is:
 1. An effervescent composition comprising: (a) abisphosphonate, (b) an acid component, and (c) an alkaline effervescingcomponent, wherein the composition when dissolved in water produces asolution having a buffered pH of about 3 to about 6.5.
 2. Theeffervescent composition of claim 1, further comprising an anti-ulceragent.
 3. The composition of claim 2, wherein the anti-ulcer agent is anH₂-antagonist.
 4. The composition of claim 3, wherein the H₂-antagonistis selected from the group consisting of ranitidine, cimetidine,famotidine, nizatidine, and combinations thereof.
 5. The composition ofclaim 2, wherein the anti-ulcer agent is a proton pump inhibitor.
 6. Thecomposition of claim 5, wherein the proton pump inhibitor is selectedfrom the group consisting of omeprazole, pantoprazole, lansoprazole,rabeprazole, and combinations thereof.
 7. The composition of claim 2,wherein the anti-ulcer agent comprises at least one H₂-antagonist and atleast one proton pump inhibitor.
 8. The composition of claim 1, whereinthe bisphosphonate is selected from the group consisting of etidronate,risedronate, ibandronate, alendronate, and combinations thereof.
 9. Thecomposition of claim 1, wherein the bisphosphonate is etidronate. 10.The composition of claim 1, wherein the bisphosphonate is alendronate.11. The composition of claim 1, wherein the bisphosphonate isibandronate.
 12. The composition of claim 1, wherein the bisphosphonateis residronate.
 13. The composition of claim 1, wherein the dissolvedbuffered solution is capable of mediating the pH of a patient's stomachfor at least about 15 minutes or more.
 14. The composition of claim 1,wherein the acid component comprises citric acid.
 15. The composition ofclaim 1, wherein the alkaline effervescing component comprises acarbonate salt and a bicarbonate salt.
 16. The composition of claim 1,wherein the acid component and the alkaline effervescing component areat least partially reacted with each other during granulation with thebisphosphonate.
 17. The composition of claim 1, further comprising asweetener or flavorant.
 18. The composition of claim 1, furthercomprising a solubilizing agent.
 19. The composition of claim 18,wherein the solubilizing agent is selected from the group consisting ofpolyvinylpyrrolidones, polyethylene glycols, dextrans, and combinationsthereof.
 20. The composition of claim 1, wherein the acid componentcomprises a non-zero amount of acid equivalents and the solutioncomprises an amount of a fully deprotonated salt of the acid componentthat is at least about 1.5 times the amount of acid equivalents.
 21. Aneffervescent composition comprising: (a) a bisphosphonate, (b) ananti-ulcer agent, (c) an acid component, (d) an alkaline effervescingcomponent, and, optionally, one or more of the following ingredientsselected from: (e) a sweetener, (f) a flavorant, and (g) a solubilizingagent.
 22. The effervescent composition of claim 21, wherein the acidcomponent and the alkaline effervescing component are at least partiallyreacted with each other during granulation with the bisphosphonateand/or the anti-ulcer agent.
 23. The composition of claim 21, whereinthe effervescent composition comprises: (a) about 0.1% to about 19%bisphosphonate, (b) about 0.5% to about 50% anti-ulcer agent, (c) about15% to about 60% acid component (d) about 20% to about 70% alkalineeffervescing component, (e) about 0% to about 5% sweetener, (f) about 0%to about 10% flavorant, and (g) about 0% to about 10% solubilizingagent, wherein the percent amounts are based on the total weight of thecomposition.
 24. The composition of claim 23, wherein the bisphosphonateis etidronate.
 25. An effervescent composition comprising: (a) amicroencapsulated bisphosphonate, (b) an acid component, (c) an alkalineeffervescing component, and optionally (d) an anti-ulcer agent.
 26. Theeffervescent composition of claim 25, wherein the bisphosphonate ismicroencapsulated in a cellulosic, gum, or wax coating.
 27. A method oftreating osteoporosis in a mammal comprising: (a) combining anosteoporosis-treating effective amount of the composition of claim 1with water to form at least a partial solution; and (b) administeringthe solution to the mammal orally.
 28. The method of claim 27, whereinadministration of the solution to the mammal produces a stomach pH of atleast about 3 or greater in the mammal.
 29. The method of claim 27,wherein the composition is administered daily, weekly, twice weekly,thrice weekly, biweekly, monthly, or every other month.
 30. The methodof claim 27, wherein the bisphosphonate is alendronate, and the amountof the alendronate to be administered weekly is about 10 mg to about 15mg.
 31. The method of claim 27, wherein the bisphosphonate isalendronate, and the amount of the alendronate to be administeredmonthly is about 50 mg to about 120 mg.
 32. The method of claim 27,wherein the bisphosphonate is alendronate, and the amount of thealendronate to be administered every other month is about 100 mg toabout 300 mg.
 33. A method of inhibiting bone resorption in a mammalcomprising: (a) combining a bone resorption inhibiting amount of thecomposition of claim 1 with water to form at least a partial solution,and (b) administering the solution to the mammal orally.
 34. The methodof claim 33, wherein administration of the solution to the mammalproduces a stomach pH of at least about 3 or greater in the mammal. 35.A method of treating osteoporosis in a mammal comprising: (a) combiningan osteoporosis-treating effective amount of the composition of claim 21with water to form at least a partial solution; and (b) administeringthe solution to the mammal orally.
 36. The method of claim 35, whereinadministration of the solution to the mammal produces a stomach pH of atleast about 3 or greater in the mammal.
 37. A method of inhibiting boneresorption in a mammal comprising: (a) combining a bone resorptioninhibiting amount of the composition of claim 21 with water to form atleast a partial solution, and (b) administering the solution to themammal orally.
 38. The method of claim 37, wherein administration of thesolution to the mammal produces a stomach pH of at least about 3 orgreater in the mammal.
 39. A method of treating osteoporosis in a mammalcomprising: (a) combining an osteoporosis-treating effective amount ofthe composition of claim 25 with water to form at least a partialsolution; and (b) administering the solution to the mammal orally. 40.The method of claim 39, wherein administration of the solution to themammal produces a stomach pH of at least about 3 or greater in themammal.
 41. A method of inhibiting bone resorption in a mammalcomprising: (a) combining a bone resorption inhibiting amount of thecomposition of claim 25 with water to form at least a partial solution,and (b) administering the solution to the mammal orally.
 42. The methodof claim 41, wherein administration of the solution to the mammalproduces a stomach pH of at least about 3 or greater in the mammal.